Document Detail

Down-regulation of platelet-derived growth factor-D inhibits cell growth and angiogenesis through inactivation of Notch-1 and nuclear factor-kappaB signaling.
MedLine Citation:
PMID:  18056465     Owner:  NLM     Status:  MEDLINE    
Platelet-derived growth factor-D (PDGF-D) signaling plays critical roles in the pathogenesis and progression of human malignancies; however, the precise mechanism by which PDGF-D causes tumor cell invasion and angiogenesis remain unclear. Because Notch-1, nuclear factor-kappaB (NF-kappaB), vascular endothelial growth factor (VEGF), and matrix metalloproteinases (MMP) are critically involved in the processes of tumor cell invasion and metastasis, we investigated whether PDGF-D down-regulation could be mechanistically associated with the down-regulation of Notch-1, NF-kappaB, VEGF, and MMP-9, resulting in the inhibition of tumor cell invasion and angiogenesis. Our data showed that down-regulation of PDGF-D leads to the inactivation of Notch-1 and NF-kappaB DNA-binding activity and, in turn, down regulates the expression of its target genes, such as VEGF and MMP-9. We also found that the down-regulation of PDGF-D by small interfering RNA (siRNA) decreased tumor cell invasion, whereas PDGF-D overexpression by cDNA transfection led to increased cell invasion. Consistent with these results, we also found that the down-regulation of PDGF-D not only decreased MMP-9 mRNA and its protein expression but also inhibited the processing of pro-MMP-9 protein to its active form. Moreover, conditioned medium from PDGF-D siRNA-transfected cells showed reduced levels of VEGF and, in turn, inhibited the tube formation of human umbilical vascular endothelial cells, suggesting that down-regulation of PDGF-D leads to the inhibition of angiogenesis. Taken together, we conclude that the down-regulation of PDGF-D by novel approaches could lead to the down-regulation of Notch-1 and, in turn, inactivate NF-kappaB and its target genes (i.e., MMP-9 and VEGF), resulting in the inhibition of invasion and angiogenesis.
Zhiwei Wang; Dejuan Kong; Sanjeev Banerjee; Yiwei Li; N Volkan Adsay; James Abbruzzese; Fazlul H Sarkar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  67     ISSN:  1538-7445     ISO Abbreviation:  Cancer Res.     Publication Date:  2007 Dec 
Date Detail:
Created Date:  2007-12-06     Completed Date:  2008-01-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  11377-85     Citation Subset:  IM    
Department of Pathology, Karmanos Cancer Institute, Wayne State University, 9374 Scott Hall, 540 East Canfield, Detroit, MI 48201, USA.
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MeSH Terms
Adenocarcinoma / blood supply,  metabolism,  prevention & control
Apoptosis / physiology
Blotting, Western
Cell Movement
Cell Proliferation*
Electrophoretic Mobility Shift Assay
Endothelium, Vascular / cytology,  metabolism
Fluorescent Antibody Technique
Immunoenzyme Techniques
Lymphokines / antagonists & inhibitors*,  genetics,  metabolism
Matrix Metalloproteinase 9 / antagonists & inhibitors,  genetics,  metabolism
NF-kappa B / antagonists & inhibitors*,  genetics,  metabolism
Neoplasm Invasiveness / pathology
Neovascularization, Pathologic / pathology
Pancreatic Neoplasms / blood supply*,  metabolism*,  prevention & control
Pancreatitis, Chronic / genetics,  prevention & control
Platelet-Derived Growth Factor / antagonists & inhibitors*,  genetics,  metabolism
RNA, Small Interfering / pharmacology
Receptor, Notch1 / antagonists & inhibitors*,  genetics,  metabolism
Signal Transduction
Transcription, Genetic
Umbilical Veins / cytology,  metabolism
Vascular Endothelial Growth Factor A / antagonists & inhibitors,  genetics,  metabolism
Grant Support
1P20-CA010193-01/CA/NCI NIH HHS; 5R01CA101870-05/CA/NCI NIH HHS
Reg. No./Substance:
0/Lymphokines; 0/NF-kappa B; 0/NOTCH1 protein, human; 0/PDGFD protein, human; 0/Platelet-Derived Growth Factor; 0/RNA, Small Interfering; 0/Receptor, Notch1; 0/VEGFA protein, human; 0/Vascular Endothelial Growth Factor A; EC Metalloproteinase 9

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